Kidney stone disease is frequent, and increasing, and has an unacceptable recurrence rate. Most stones are made of calcium oxalate (CaOx), and urinary oxalate is a major risk factor. There is not yet an effective treatment for stone disease that can target urinary oxalate. Our long-term goal is to find a way to prevent stone formation in common idiopathic stone disease, and kidney calcification in the rare but most malignant form of stone disease, primary hyperoxaluria (PH). Pyridoxamine (PM) is a derivative of vitamin B6 that is present in small amounts in normal humans. Its chemical nature allows it to trap the precursors of oxalate biosynthesis (glyoxylate and glycolaldehyde). This process is well demonstrated in vitro. In our preliminary animal data, we showed (1) that PM can significantly lower oxalate excretion in normal and hyperoxaluric rats; and (2) that PM can dramatically decrease the development of CaOx calcification in these hyperoxaluric rats. Other clinical trials have shown that pyridoxamine is non-toxic in humans. We propose that PM will reduce human oxalate synthesis that occurs primarily in the detoxification compartment of liver cells (the peroxisome) in humans. This will decrease oxalate excretion, and therefore reduce a risk factor for kidney stone formation. The primary goal of the proposed study is to show that it is feasible to reduce urinary oxalate excretion in humans by using PM. The Specific Aims of the study will be (1) to evaluate PM treatment in people with kidney stones without hyperoxaluria. This is a placebo- controlled, double-blinded, crossover design. We expect to find that urinary oxalate will be reduced while other factors will not change. Therefore, the supersaturation state, which strongly influences stone formation, will be significantly improved. Patients from stone clinics are available for this study and are highly motivated to participate. (2) We will also study patients with Primary Hyperoxaluria (PH), a genetic disease that usually results in kidney failure at an early age. Here, we will explore the feasibility of lowering the massive oxalate generation derived from endogenous synthesis. If it is successful, PM will offer the first significant non-transplant treatment for this frequently fatal disease. To directly test the model of PM action we also plan (3) to characterize the way that PM forms complexes with the precursors of oxalate, glyoxylate and glycolaldehyde, in urine and serum of these patients. The public health implications of this study are in its contributions to preventing common kidney stone disease, and preventing kidney failure in an orphan disease, Primary Hyperoxaluria. [unreadable] [unreadable] [unreadable]